Preferential ATP-binding cassette transporter A1-mediated cholesterol efflux from late endosomes/lysosomes
Preferential ATP-binding cassette transporter A1-mediated cholesterol efflux from late endosomes/lysosomes
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DOI：
10.1074/jbc.m107938200
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发表时间：
2001-11-23
影响因子：
4.8
通讯作者：
Tall, AR
中科院分区：
文献类型：
--
作者：
Chen, W;Sun, Y;Tall, AR
最近，ATP结合盒转运蛋白Al（ABCA 1），在丹吉尔病的缺陷分子，已被证明刺激磷脂和胆固醇流出到载脂蛋白A-I（apoA-I），然而，鲜为人知的是，关于细胞胆固醇池作为来源的胆固醇ABCA 1介导的流出。我们观察到，与用含10%胎牛血清的[H-3]胆固醇标记的细胞相比，用[H-3]胆固醇/乙酰基低密度脂蛋白标记的小鼠腹腔巨噬细胞（其中胆固醇在晚期内体和溶酶体中积累）的同位素和质量胆固醇流出水平更高，这表明晚期内体/溶酶体作为ABCA 1介导的胆固醇流出的优先来源。与这一想法一致，来自Niemann-Pick C1小鼠的巨噬细胞不能从晚期内体/溶酶体排出胆固醇，显示出胆固醇流出至apoA-I的严重缺陷。相比之下，尼曼-皮克C1巨噬细胞中磷脂流出至apoA-I是正常的，质膜胆固醇标记后胆固醇流出也是正常的。这些结果表明，胆固醇沉积在晚期内体/溶酶体优先作为ABCA 1介导的胆固醇流出的胆固醇来源。
Recently, ATP-binding cassette transporter Al (ABCA1), the defective molecule in Tangier disease, has been shown to stimulate phospholipid and cholesterol efflux to apolipoprotein A-I (apoA-I); however, little is known concerning the cellular cholesterol pools that act as the source of cholesterol for ABCA1-mediated efflux. We observed a higher level of isotopic and mass cholesterol efflux from mouse peritoneal macrophages labeled with [H-3]cholesterol/acetyl low density lipoprotein (where cholesterol accumulates in late endosomes and lysosomes) compared with cells labeled with [H-3]cholesterol with 10% fetal bovine serum, suggesting that late endosomes/lysosomes act as a preferential source of cholesterol for ABCA1-mediated efflux. Consistent with this idea, macrophages from Niemann-Pick C1 mice that have an inability to exit cholesterol from late endosomes/lysosomes showed a profound defect in cholesterol efflux to apoA-I. In contrast, phospholipid efflux to apoA-I was normal in Niemann-Pick C1 macrophages, as was cholesterol efflux following plasma membrane cholesterol labeling. These results suggest that cholesterol deposited in late endosomes/lysosomes preferentially acts as a source of cholesterol for ABCA1-mediated cholesterol efflux.